PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (ICC) is a deadly liver cancer which has been rising in incidence over several decades. The overarching goal of this proposal is to evaluate novel therapeutic strategies for the subset of ICC harboring mutations in isocitrate dehydrogenase 1 (IDH1), the most common oncogenic driver in this disease. In early phase clinical trials, pharmacologic inhibitors of mutant IDH provided clinical benefit in some patients, but their mechanism of action remains poorly understood due to a paucity of on-treatment biopsy tissue and relevant model systems. To overcome this hurdle, a protocol to maintain the viability and original architecture of resected ICC tumors as `tumor slice cultures' (TSCs) and evaluate their response to targeted therapies within their native microenvironment has been developed. In the proposal attached, 100 TSCs will be generated for each of the ~50 resected ICCs over the next two years, anticipating 10-15 IDH mutant ICC tumors. We will then assess their response to mutant IDH inhibition by monitoring proliferation, apoptosis, viability and the expression of relevant biomarkers. Finally, we will evaluate possible combinatorial strategies based on top `hits' from unbiased drug screens of IDH mutant preclinical models. Responses will be correlated with underlying tumor genetics and compared to those of IDH wild-type tumors. Overall, these data will serve as proof of concept for a long-term study exploiting ICC TSCs to elucidate the mechanisms underlying IDH inhibition in ICC, identify predictive biomarkers of response and resistance and establish effective combinatorial strategies for subsequent evaluation in a clinical trial setting.